Risky Business

St. Jude scientists have found one potential reason why Hispanic children have a higher risk of developing acute lymphoblastic leukemia when compared to African-American or white children.

Why are some children at higher risk of getting leukemia?

Children of any ethnicity can be struck with acute lymphoblastic leukemia (ALL), the most common type of pediatric cancer. But scientists have long known that Hispanic children are at higher risk of developing ALL than white or African-American kids.

The reason for this discrepancy has remained a mystery. But scientists at St. Jude Children’s Research Hospital have recently started to uncover some important clues, buried deep within the DNA that children inherit from their parents.

“For many years, people suspected that there was a genetic basis to susceptibility for ALL,” says Jun Yang, PhD, a lead researcher in the recent work. “For example, in identical twins with the same genetic makeup, if one twin has leukemia, the risk of the second twin developing it is much higher.”

However, Yang says, it has been challenging to find the subtle DNA differences that make children in some ethnic groups more likely to develop ALL.

“Unless we study minority populations, we just won’t know what is driving the ethnic disparity in this disease,” says Jun Yang, PhD (at right), shown working with Heng Xu, PhD, of St. Jude Pharmaceutical Sciences.

Unexpected risk

To search for these differences, Yang and his collaborators painstakingly combed through the DNA of thousands of children with ALL, comparing their entire genetic makeups to those of individuals without ALL. The scientists were trying to find small variations that could account for differences in disease risk.

What they discovered was striking: For all ethnic groups, inheriting high-risk versions of just four genes was associated with up to a ninefold higher risk of developing childhood ALL. The degree of increase in risk was unexpected for a complex disease such as ALL.

“It’s only four variants, and putting them together gives such a large effect; it’s pretty impressive,” Yang says. “I was a bit surprised at that.”

And the researchers made another key finding: Two of the high-risk gene versions were more frequently inherited by Hispanic children, pointing to at least one reason for their increased odds of developing ALL. Furthermore, these versions were least common in African Americans, who have the lowest disease risk.

“This was the first multi-ethnic, genome-wide study of this size to look at risk factors for pediatric ALL,” Yang says. “Unless we study minority populations, we just won’t know what is driving the ethnic disparity in this disease.”

Tailoring therapy

Finding these risk factors is a first step toward creating new treatments tailored for individual ALL patients based on their genetic makeup. But with 94 percent of St. Jude ALL patients already becoming long-term survivors, how much better can therapy become?

“ALL is a tremendously successful story in our battle against cancer,” Yang says. “However, the conventional chemotherapy we use on young patients can be ‘big cannons’ with a lot of side effects.

“What we need to do next is to develop more precise, targeted therapy for leukemia. And how do we do that? We need to learn more about the biology of the disease,” he continues.

“Now we know that these genes are important, which tells us a lot about the process by which leukemia actually develops. And that gives us a hint as to what we should be targeting with new therapies.”

Debt of gratitude

The collaborative research environment at St. Jude was key to the success of this large-scale endeavor.

“We had extensive collaboration within St. Jude—biostatisticians, pathologists, oncologists and scientists who are studying leukemia biology and pharmacogenomics,” Yang says. “We also reached out to the Children’s Oncology Group, which treats pediatric cancer patients around the country.”

And, he adds, there were other collaborators with a vitally important role.

“None of this could have happened without the patients and their parents,” he says. “They are extremely generous, working with us to help the research move forward. They understand how important the work is—how it can help not only children undergoing treatment, but also future patients.”

An event that occurred early in Yang’s research career continues to provide him with motivation.

“I was giving a laboratory tour once and met a St. Jude patient with a brain tumor, who said she wanted to do research someday to help other kids,” he recalls.

“As they were leaving, her mom came up to me and held my hand. She said, ‘I pray every day that you get to do the work you’re doing, because that is the only hope for my child.’

“It was emotional,” Yang says, “and I understood more than ever the importance of the work we do at St. Jude.”